Abstract It is now well established that PTSD is a major health issue in military personnel. Although a proportion of returning veterans from the Gulf war and war on terrorism complain of bone aches, nothing is known about the impact of PTSD on the skeletal system. In this study, our focus is on PTSD effects on bone formation since skeletal injury is one of the common injuries among military personnel that require rehabilitation for restoration of function and since a previous study demonstrated that Gulf war veterans exhibit a deficiency in bone formation. Furthermore, it is well established that PTSD leads to the activation of sympathetic nervous system (SNS) and changes in hypothalamus-pituitary-adrenal (HPA) axis. The changes in HPA axis can influence bone formation by regulating cortisol as well as growth hormone (GH), two major systemic regulators of bone. In terms of the molecular pathway by which PTSD-induced changes in HPA axis could influence bone, we have implicated IGF-I for several reasons. First, IGF-I is critically important in bone formation process and the actions of GH and cortisol on bone involve IGF-I. Second, IGF-I is involved in mediating the skeletal anabolic effects of exercise, a key physiological regulator of bone formation. Third, our preliminary data show that chronic stress inhibits IGF-I expression and bone formation in vivo. Based on these rationale, we propose to test the following hypotheses in this study: 1) PTSD influences development of peak bone mass and susceptibility to osteoporosis;2) PTSD exerts significant negative impact on the ability of skeleton to build new bone in response to mechanical strain;and 3) PTSD effect on bone formation is mediated in part via down-regulation of IGF-I action. To test if PTSD- induced changes in neuroendocrine hormones will have a negative impact on acquisition of peak bone mass, we will subject prepubertal mice to a single traumatic stress and evaluate the consequence of PTSD on peak bone mass and strength at 4 months of age when majority of bone has formed. To test if PTSD exerts negative effects on mechanical loading-induced bone formation, we will evaluate the consequence of traumatic stress on mechanical loading-induced increase in the number and activity of osteoblasts in mice. Tibial axial loading model will be used to evaluate the anabolic effects of mechanical loading on bone formation in PTSD and non-PTSD mice. We will next evaluate if pharmacological intervention to ameliorate PTSD symptoms is effective in rescuing the ability of skeleton to respond to mechanical strain. To test the hypothesis that PTSD effects on bone are mediated via decreased IGF-I action, we will examine the correlation between changes in mechanical loading-induced expression levels of IGF system components and bone formation markers. To establish a causal role for impaired IGF-I action in mediating PTSD effects, we will use a transgenic mouse model with increased IGF-I action to rescue PTSD effects on the skeleton. An understanding of the molecular pathway by which PTSD influences bone formation process will lead to therapeutic approaches to neutralize PTSD effect and thereby improve skeletal health in military personnel. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Post traumatic stress disorder (PTSD) is the most prevalent mental disorder arising from combat. We know very little on the molecular mechanisms of the PTSD disease process because of the complexity and variability of PTSD symptoms and lack of experimental studies testing the cause and effect relationship between biochemical changes and PTSD symptoms. This study will test how PTSD influences bone formation process and whether insulin-like growth factor regulatory system is involved in mediating PTSD effects on bone formation process in an experimental animal model using state-of-the art techniques. The proposed basic research to identify the molecular pathways for PTSD effects on bone will lead to the future development of effective therapies to minimize the negative effects of PTSD on bone and improve the general well-being in the VA and in the general population.